Total mesorectal excision after rectal-sparing approach in locally advanced rectal cancer patients after neoadjuvant treatment: a high volume center experience

Background: In patient with a complete or near-complete clinical response after neoadjuvant treatment for locally advanced rectal cancer, the organ-sparing approach [watch & wait (W&W) or local excision (LE)] is a possible alternative to major rectal resection. Although, in case of local recurrence or regrowth, after these treatments, a total mesorectal excision (TME) can be operated. Method: In this retrospective study, we selected 120 patients with locally advanced rectal cancer (LARC) who had a complete or near-complete clinical response after neoadjuvant treatment, from June 2011 to June 2021. Among them, 41 patients were managed by W&W approach, whereas 79 patients were managed by LE. Twenty-three patients underwent salvage TME for an unfavorable histology after LE (11 patients) or a local recurrence/regrowth (seven patients in LE group – five patients in W&W group), with a median follow-up of 42 months. Results: Following salvage TME, no patients died within 30 days; serious adverse events occurred in four patients; 8 (34.8%) patients had a definitive stoma; 8 (34.8%) patients undergone to major surgery for unfavorable histology after LE – a complete response was confirmed. Conclusion: Notably active surveillance after rectal sparing allows prompt identifying signs of regrowth or relapse leading to a radical TME. Rectal sparing is a possible strategy for LARC patients although an active surveillance is necessary.


Introduction
The treatment of rectal cancer needs a multidisciplinary approach performed by a highly specialized multidisciplinary team.Neoadjuvant therapy (NT) -radio or chemoradiotherapy -associated with total mesorectal excision (TME), is the standard of care for locally advanced rectal cancer (LARC) (stage II/III) patients.2][3] TME, even more if preceded by neoadjuvant treatment, is associated with a still measurable postoperative mortality, high rates of morbidity, as genitourinary and sexual dysfunction, long-term functional bowel disturbance and altered fecal continence, stoma complications, and a related negative impact on quality of life Total mesorectal excision after rectal-sparing approach in locally advanced rectal cancer patients after neoadjuvant treatment: a high volume center experience 2 journals.sagepub.com/home/cmg 1][12][13][14] This is associated with favorable long-term patient outcomes compared with those without complete response. 11,151][22][23] Therefore, when a rectalsparing approach is realized, an intensive surveillance of these patients is required and a salvage TME is mandatory for an unfavorable histology after LE or in case of local recurrence or regrowth.
In this retrospective study, we described our experience in rectal-sparing strategy evaluating results and risk in terms of tumor recurrence and evaluated the TME outcome when performed after this approach.

Materials and methods
From June 2011 to June 2021, we treated 931 patients with LARC by NT.Patients with any T and N+ clinical stage, and/or with circumferential resection margin (CRM) ⩽ 1 mm (by magnetic resonance imaging or endorectal ultrasound for the patients with persistent contraindications to MRI), underwent to radiochemotherapy (50 Gy with concomitant capecitabine at a daily dose of 825 mg/m 2 /12 h); patients with cT2/3, N0, < 5 cm from anal verge and patients facing tumors with enlarged nodes and/or CRM positive who resulted unfit for chemo-radiation, underwent to short course of radiotherapy (25 Gy).The initial stage of patients is reported in Table 1.
All consecutive patients managed by rectal-sparing strategy, due to a complete or near-complete clinical and radiological response following NT for LARC, from June 2011 to June 2021, were registered in a prospective database.The National Cancer Institute of Naples Ethical Committee board approved the use of data for this retrospective study.
The response evaluation following NT was performed after 8 weeks, from completion of therapies and it included: digital rectal examination, carcinoembryonic antigen test, rigid proctoscopy, whole-body computed tomography (CT) and pelvic MRI.
All cases were rediscussed in a multidisciplinary team meeting (MDT).
The criteria identifying a near complete clinical response were considered 24,25 : -Minor mucosal irregularity and movable, felt on digital exam -Small superficial ulceration at proctoscopy (<2 cm) -Predominant fibrosis (>75%) without lymph node metastasis on MRI assessment All patients encountered these criteria and agreed to a LE strategy (79 patients) were managed by full-thickness excision.
Clinical complete response was defined by 24,25 : -The presence of complete tumor regression without lymph node metastasis at MRI evaluation -White scars or telangiectasia of the mucosa, the absence of mass, ulceration, or stenosis at proctoscopy All patients encountered these criteria and agreed to W&W (41 patients) were approached by W&W strategy.
Patients with poor response after NT, lymph node involvement, or metastases at restaging imaging after NT were excluded.
Salvage TME was performed in (Figure 1): -Patients with histopathologic evidence of ypT ⩾ 2 ± R ⩾ 1, after LE -Patients with local recurrence or regrowth during follow-up TNM classification was utilized 26 to stage tumors before and after NT.
Pathologic assessment of tumor regression was carried out according to the Mandard's classification. 27ostoperative morbidity was assessed according to the Clavien-Dindo classification. 28llow-up Our follow-up strategy included clinical examination, carcinoembryonic antigen test, and rigid proctoscopy in every outpatient visit, every 3 months during the first 2 years, then every 6 months in the following 3 years, and then every 12 months in the following 5 years.
The radiological follow-up included MRI every 6 months and whole-body CT every year for distant metastases.
Colonoscopy was performed after 1 year and then every 2 years.
Local regrowth and local recurrence were defined as any reappearance of tumor at the original tumor location or nodal recurrence in the pelvis.
Distant metastases were defined as the presence of metastatic disease, as identified by CT.

Statistical analysis
Yates' chi square test was employed to analyze differences of categorical variable prevalence, whereas the nonparametric Kruskal-Wallis test was used to test for statistically significant differences between the median values of the continuous variables.Disease-free survival rate as the percentage of treated patients who still have no evidence of disease at a certain period of time after treatment.Overall survival rate was  A p-value < 0.05 was considered as statistically significant.
Statistical analysis was obtained by means of the Statistic Toolbox of MATLAB (The MathWorks, Inc., Natick, MA, USA).

Results
During a frame time of 10 years, a total of 120 patients (Figure 1) treated by NT for LARC had a complete or near-complete clinical response at restaging.
Study group included 35 females and 85 males.
Salvage TME after the rectal-sparing approach was performed in 23 patients (Table 2) with the following indications: -Eleven patients with evidence of ypT ⩾ 2 ± R ⩾ 1, at histopathologic exam after LE. -Seven patients with local recurrence after LE during follow-up.
-Five patients with local regrowth after W&W strategy during follow-up.
Five exits were recorded in the LE group in the 12-68 month range.No exit was recorded in the W&W group.The 5-year overall survival rate was 97.5%.
In Figure 1, we outline the flowchart of the study.
LE was performed either with the traditional transanal excision (TAE) or by a minimally invasive approach by transanal endoscopic microsurgery (TEM) or transanal minimally invasive surgery (TAMIS).Median operative time for full thickness local excision (LE) of residual tumor has been 57 (range 10-145) min; hospital stay was 3 (range 1-16) days.Serious intraoperative complications were peritoneal reflection opening (two patients -2.5%), treated by transanal suture; in only three patients, there was a nonhealing rectal wound with a mild discomfort resulted into at most 3 weeks; no serious postoperative adverse events (Clavien-Dindo ⩾ 3) occurred (Table 3).
In 25 (31.6%)patients, histology showed ypT ⩾ 2 and/or R ⩾ 1 (1 patient with ypT1 R1, 24 patients with ypT2).Out of these, radical surgical salvage was performed on 11 patients; 14 patients did not undergo to major surgery: eight patients were considered unfit for a completion surgery and six patients refused major surgery.We included these patients in the results of the follow-up.
TME for unfavorable histopathologic exam after LE.
We performed TME in 11 patients with unfavorable histopathologic results following LE: ypT ⩾ 2 and/or R ⩾ 1 (Table 4).In three patients, the recurrence appeared within 12 months, in four patients within 24 months.Distant metastases were detected in 5 (7.3%) patients.The disease-free survival at 48 months was 82.35%.
All patients with local recurrence underwent completion TME.Two patients underwent LAR resection with colorectal anastomoses, four patients underwent abdominoperineal rectal resection, and one patient underwent low anterior rectal resection with colostomy (Table 5).
The major complications were: postoperative anastomotic dehiscence (one patient) treated with conservative approach, and a severe heart failure in one patient.
Final histological exam evidenced ypT1N0 in three patients, ypT2N0 in one patient, ypT3N0 in one patient, ypT4N0 in one patient, and ypT0N0V1 in one patient.
Mesorectal excision was considered curative in all patients.In fact, no patients had R1 margins of resection.

Discussion
In recent years, the organ-sparing approach in patients with complete or near-complete response to NT is becoming an alternative treatment to TME.In patients with local recurrence or regrowth or unfavorable histology after organ sparing, the major surgery is still considered a standard of care.0][31][32][33][34] As in many guidelines, an organ-sparing approach has to be considered only within clinical trials and in centers with experienced multidisciplinary teams.Local recurrence/ regrowth rates within 2 years following rectal sparing are described in a range from 7 to 23%. 10,14,35,36owever, there is an open issue of whether the TME protracted interval from NT could cause excessive fibrosis that may lead to increased surgical complexity and postoperative morbidity.
[39] The aim of the present study was to report the outcomes of TME after organ-sparing approaches to evaluate oncological safety and surgical feasibility.
In our experience, 18 patients underwent a complete TME followed by a local excision and 5 patients followed the wait and watch strategy.
Among patients who agreed to undergo the complete TME surgery for unfavorable histopathology after LE, only 3 of 11 patients showed residual cancer at their final histopathology evaluation.The clinical implication is relevant since eight patients underwent an anterior rectal resection with the absence of residual cancer at the final histopathology, also placing a reflection on the real need, in some cases, to proceed with salvage TME.
In our study, seven patients (10.3%) showed recurrence after LE, requiring a subsequent completion TME.This seems to be in line with other authors who describe a recurrence rate of 5-15%. 40,41Other authors 42 describe different recurrence rate (22%) following rectal sparing.These very broad differences regarding recurrence rates suggest that a precise and communal management for rectal sparing following NT does not yet exist.
All recurring tumors were salvageable by TME.The mean time to the recurrence following LE was 13 months (range 8-21), with a higher rate of local recurrences within 2 years.High rates (42.8%) of local recurrence have been found in patients with ypT2 following LE that refused early salvage surgery.
In our experience, five patients showed regrowth after the W&W approach.The mean time to the local regrowth was 22 months (range 7-56 months) with a higher rate (40%) within the first year; all tumors were salvageable by TME.Two patients (40%) reported an ypT1N0 residual cancer at final histopathology, opening the prospective to evaluate LE for the regrowth too.
We described a postoperative complications rate of 16.6% considering only TME following local excision.8][39] This result in our clinical records can be related to the absence of a standard colorectal anastomosis; in six patients, we performed a coloanal pull through anastomosis, and in eight patients we performed a permanent colostomy.However, in our series, all patients had a good quality of the mesorectal plane.Colostomy-free rate was 72.7%.
Regarding the need for a permanent colostomy, it is difficult to establish as this depends on the previous surgery or the height of the primary tumor.In our experience, for two patients the lesion was on the anorectal ring (one of these patients was 80 years old), and in another case, the lesion was 3 cm from the anorectal ring, in a patient with a disabling neuropathic pathology.These pre-existing conditions also guided our surgical decision for a permanent colostomy.
The organ preservation rate is 80.8%, and it is similar to the oldest datasets, 43,44 despite geographic and patient heterogeneity.Other data series report a higher organ preservation rate. 45,46he reasons for this are undoubtedly multifactorial, including selection bias, the cohort volume, Our data suggest that patients with an accurate evaluation of complete or near-complete response and then treated with the organ-sparing strategy have no oncological disadvantage neither in case of recurrence, and the surgical and oncological outcomes seem to be comparable to those described for patients who underwent to primary TME surgery, with a complete or near-complete pathologic response.
We support as the salvage TME does not invalidate the oncological outcomes; the prognosis for rectal cancer remain relate with the stage of the tumor, following NT.
In this scenario, it is clear as an active follow-up is necessary.

Figure 1 .
Figure 1.Flowchart of the study.

Table 1 .
Pre NT stage and neoadjuvant treatments.

Table 2 .
Clinical and demographic characteristics of patients.

Table 3 .
Results about LE group.

Table 4 .
TME for unfavorable histopathology after LE.

Table 5 .
TME for recurrence after LE.
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39. Eid Y, AlvesA, Lubrano J, et al.Does previous transanal excision for early rectal cancer impair surgical outcomes and pathologic findings of completion total mesorectal excision?Results of a systematic review of the literature.J Visc Surg 2018; 155: 445-452.